Reduced expression of plakoglobin indicates an unfavorable prognosis in subsets of patients with non-small-cell lung cancer.

Pantel, Klaus; Passlick, Bernward; Vogt, Juergen; Stosiek, P; Angstwurm, Matthias; Seen-Hibler, Rita; Häußinger, K.; Thetter, O.; Izbicki, J. R.; Riethmüller, Gert

doi:10.1200/jco.1998.16.4.1407

Cited by 56 publications

(41 citation statements)

References 24 publications

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“…Moreover, loss of heterozygosity at the plakoglobin locus has been observed in human breast and ovarian cancer (Aberle et al, 1995), and it has been proposed that plakoglobin can act as a tumor suppressor (Simcha et al, 1996). Consistent with this proposal, reduced levels of plakoglobin RNA have been found in cervical carcinoma (Denk et al, 1997) and are linked to unfavorable prognosis in patients with non-small cell lung carcinoma (Pantel et al, 1998).…”

Section: Introductionsupporting

confidence: 67%

A comparative evaluation of β-catenin and plakoglobin signaling activity

et al. 2000

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Vertebrates have two Armadillo-like proteins, b-catenin and plakoglobin. Mutant forms of b-catenin with oncogenic activity are found in many human tumors, but plakoglobin mutations are not commonly found. In fact, plakoglobin has been proposed to suppress tumorigenesis. To assess di erences between b-catenin and plakoglobin, we compared several of their biochemical properties. After transient transfection of 293T cells with an expression vector encoding either of the two proteins, soluble wild type b-catenin does not signi®-cantly accumulate, whereas soluble wild type plakoglobin is readily detected. As anticipated, b-catenin is stabilized by the oncogenic mutation S37A; however, the analogous mutation in plakoglobin (S28A) does not alter its halflife. S37A-b-catenin activates a TCF/LEF-dependent reporter 20-fold more potently than wild type b-catenin, and *5-fold more potently than wild type or S28A plakoglobin. These di erences may be attributable to an enhanced a nity of S37A b-catenin for LEF1 and TCF4, as observed here by immunoprecipitation assays. We show that the carboxyl-terminal domain is largely responsible for the di erence in signaling and that the Armadillo repeats account for the remainder of the di erence. The relatively weak signaling by plakoglobin and the failure of the S28A mutation to enhance its stability, may explain why plakoglobin mutations are infrequent in malignancies. Oncogene (2000) 19, 5720 ± 5728.

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Section: Introductionsupporting

confidence: 67%

A comparative evaluation of β-catenin and plakoglobin signaling activity

et al. 2000

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“…One of the causes of AJ dysfunction often detected in tumor cells of epithelial origin is decreased expression of E-cadherin, ␣-, and ␥-catenin (plakoglobin) (15,16). Upon examination of the expression of components of the AJs, we observed that neither mRNA nor protein levels of E-cadherin, ␣-catenin, and ␤-catenin were affected by autocrine production of hGH (Fig.…”

Section: Resultsmentioning

confidence: 83%

Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone

Mukhina

Mertani

Guo

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

141

118

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We report here that autocrine production of human growth hormone (hGH) results in a phenotypic conversion of mammary carcinoma cells such that they exhibit the morphological and molecular characteristics of a mesenchymal cell, including expression of fibronectin and vimentin. Autocrine production of hGH resulted in reduced plakoglobin expression and relocalization of E-cadherin to the cytoplasm, leading to dissolution of cell-cell contacts and decreased cell height. These phenotypic changes were accompanied by an increase in cell motility, elevated activity of specific matrix metalloproteinases, and an acquired ability to invade a reconstituted basement membrane. Forced expression of plakoglobin significantly decreased mammary carcinoma cell migration and invasion stimulated by autocrine hGH. In vivo, autocrine hGH stimulated local invasion of mammary carcinoma cells concomitant with a prominent stromal reaction in comparison with well delineated and capsulated growth of mammary carcinoma cells lacking autocrine production of hGH. Thus, autocrine production of hGH by mammary carcinoma cells is sufficient for generation of an invasive phenotype. Therapeutic targeting of autocrine hGH may provide a mechanistic approach to prevent metastatic extension of human mammary carcinoma. M ammary epithelial carcinoma is one of the leading causes of cancer-related mortality of female residents in Western countries, predominantly due to a high metastatic frequency (1). Identification of specific molecular determinants for metastatic mammary carcinoma and subsequent development of concordant biologic therapies are therefore of primary importance. During metastatic conversion, mammary carcinoma cells acquire the ability to invade surrounding tissue with subsequent dissemination to secondary organs. The acquisition of a migratory and invasive phenotype by cells of epithelial origin is associated with gain of mesenchymal characteristics concomitant with loss of the epithelial phenotype, a phenomenon referred to as epithelial-mesenchymal transition (2). This transition from epithelial to mesenchymal cell phenotype involves specific morphological and molecular alterations, including the loss of E-cadherin-mediated cell adhesion (2-4).The human growth hormone (hGH) gene is expressed in the normal and neoplastic human mammary epithelial cell (5, 6). Elevated hGH gene expression is observed to be associated with metastatic mammary carcinoma cells (5), suggestive of a functional contribution of autocrine hGH to the metastatic process. We have concordantly previously demonstrated that autocrine hGH dramatically enhances spreading of mammary carcinoma cells on a collagen substrate (7). These observations suggest that autocrine production of hGH may contribute to conversion of human mammary epithelial cells to a mesenchymal phenotype. We demonstrate herein that in mammary carcinoma cells with epithelial morphology, autocrine production of hGH promotes mesenchymal cellular morphology, increased cell migration, and increased matrix metallop...

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“…Plakoglobin has often been associated with tumorsuppressor activity, although the mechanisms behind this activity remain unclear (Simcha et al, 1996;Pantel et al, 1998;Parker et al, 1998;Winn et al, 2002;Reiger-Christ et al, 2005). More recently, downregulation of plakoglobin was also shown to increase the risk of pulmonary metastasis in soft tissue sarcomas (Kanazawa et al, 2008) and was associated with poor differentiation of oral squamous cell carcinoma and with lymph node metastases (Narkio-Makela et al, 2009), further supporting the idea that plakoglobin functions to suppress metastasis in addition to tumor formation.…”

Section: Plakoglobin Interacts With and Regulates Nm23mentioning

confidence: 95%

“…In contrast, plakoglobin has typically been associated with tumor/metastasis-suppressor activity, although the mechanism behind this activity is not understood (Simcha et al, 1996;Pantel et al, 1998;Parker et al, 1998;Winn et al, 2002;Reiger-Christ et al, 2005;Kanazawa et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

et al. 2010

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Plakoglobin (c-catenin) is a homolog of b-catenin with similar dual adhesive and signaling functions. The adhesive function of these proteins is mediated by their interactions with cadherins, whereas their signaling activity is regulated by association with various intracellular partners. In this respect, b-catenin has a well-defined oncogenic activity through its role in the Wnt signaling pathway, whereas plakoglobin acts as a tumor/metastasis suppressor through mechanisms that remain unclear. We previously expressed plakoglobin in SCC9 squamous carcinoma cells (SCC9-P) and observed a mesenchymalto-epidermoid transition. Comparison of the protein and RNA profiles of parental SCC9 cells and SCC9-P transfectants identified various differentially expressed proteins and transcripts, including the nonmetastatic protein 23 (Nm23). In this study, we show that Nm23-H1 mRNA and Nm23-H2 protein are increased after plakoglobin expression. Coimmunoprecipitation and confocal microscopy studies using SCC9-P and various epithelial cell lines with endogenous plakoglobin expression revealed that Nm23 interacts with plakoglobin, cadherins and a-catenin. Furthermore, Nm23-H2 is the primary isoform involved in these interactions, which occur prominently in the cytoskeleton-associated pool of cellular proteins. In addition, we show that plakoglobinNm23 interaction requires the N-terminal (a-catenin interacting) domain of plakoglobin. Our data suggest that by increasing the expression and stability of Nm23, plakoglobin has a role in regulating the metastasis suppressor activity of Nm23, which may further provide a potential mechanism for the tumor/metastasis suppressor function of plakoglobin itself.

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Reduced expression of plakoglobin indicates an unfavorable prognosis in subsets of patients with non-small-cell lung cancer.

Abstract: Deficient expression of plakoglobin appears to be an important event in the progression of NSCLC.

Cited by 56 publications

References 24 publications

A comparative evaluation of β-catenin and plakoglobin signaling activity

A comparative evaluation of β-catenin and plakoglobin signaling activity

Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

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